Sphingosine kinase-dependent regulation of pro-resolving lipid mediators in Alzheimer's disease.

The majority of peripheral and central nervous system disorders are related to hyperactive inflammatory responses, leading to irreversible and persistent cellular defects, functional impairments, and behavioral deficits. Advances in our understanding of these disorders have revealed the disruption of inflammation resolution pathways due to abrogated responses by specialized pro-resolving lipid mediators (SPMs). SPMs comprise a class of bioactive lipids and cell signaling molecules that function to resolve inflammation, pain, and function in host defense and tissue remodeling. Their cellular and systemic levels during physiology and pathology are regulated by sphingosine kinases (especially SphK1) that act by monitoring cyclooxygenase-2 (COX2), a potent inhibitor of SPMs production. This review presents the current understanding of the convergent mechanisms shared by bioactive lipids with SphK1 and COX2 in the etiology of chronic inflammatory disorders, focusing on neuroinflammation, as well as describes the translational directions of this trilogy for the treatment of Alzheimer's disease.

Novelty of Sphingolipids in the Central Nervous System Physiology and Disease: Focusing on the Sphingolipid Hypothesis of Neuroinflammation and Neurodegeneration.

For decades, lipids were confined to the field of structural biology and energetics as they were considered only structural constituents of cellular membranes and efficient sources of energy production. However, with advances in our understanding in lipidomics and improvements in the technological approaches, astounding discoveries have been made in exploring the role of lipids as signaling molecules, termed bioactive lipids. Among these bioactive lipids, sphingolipids have emerged as distinctive mediators of various cellular processes, ranging from cell growth and proliferation to cellular apoptosis, executing immune responses to regulating inflammation. Recent studies have made it clear that sphingolipids, their metabolic intermediates (ceramide, sphingosine-1-phosphate, and N-acetyl sphingosine), and enzyme systems (cyclooxygenases, sphingosine kinases, and sphingomyelinase) harbor diverse yet interconnected signaling pathways in the central nervous system (CNS), orchestrate CNS physiological processes, and participate in a plethora of neuroinflammatory and neurodegenerative disorders. Considering the unequivocal importance of sphingolipids in CNS, we review the recent discoveries detailing the major enzymes involved in sphingolipid metabolism (particularly sphingosine kinase 1), novel metabolic intermediates (N-acetyl sphingosine), and their complex interactions in CNS physiology, disruption of their functionality in neurodegenerative disorders, and therapeutic strategies targeting sphingolipids for improved drug approaches.

The blood cerebrospinal fluid barrier orchestrates immunosurveillance, immunoprotection, and immunopathology in the central nervous system.

Once characterized as an immune privileged area, recent scientific advances have demonstrated that the central nervous system (CNS) is both immunologically active and a specialized site. The anatomical and cellular features of the brain barriers, the glia limitans, and other superficial coverings of the CNS endow the brain with specificity for immune cell entry and other macro- and micro-elements to the brain. Cellular trafficking via barriers comprised of tightly junctioned non-fenestrated endothelium or tightly regulated fenestrated epithelium results in different phenotypic and cellular changes in the brain, that is, inflammatory versus regulatory changes. Based on emerging evidence, we described the unique ability of the blood cerebrospinal fluid barrier (BCSFB) to recruit, skew, and suppress immune cells. Additionally, we sum up the current knowledge on both cellular and molecular mechanisms governed by the choroid plexus and the cerebrospinal fluid at the BCSFB for immunosurveillance, immunoprotection, and immunopathology. [BMB Reports 2021; 54(4): 196-202].

Report: Metformin potential in predisposing arthralgia, type II cross reactivity secondary to group A streptococcus infection & other comorbidities in treating PCOS.

One of the most common endocrinological disorder affecting women in adolescence is Polycystic Ovarian Syndrome (PCOS). Women suffering from PCOS diagnosed with follicles in ovaries show enlarged reproductive organs with small filled follicles. Unusual bleeding, prolonged menstruation, unwanted hair growth, accumulation of fat and acne are the most common problems experienced by adolescents with PCOS. Nowadays, PCOS is treated successfully with the oral antidiabetic drug, metformin and hormone replacement therapy. Its off-label use is still controversial with unknown mechanisms due to patient risk versus benefit hypothesis by practitioners as they successfully treat PCOS in adolescents with metformin. But in few reported cases metformin has potential to induce back pain and swollen joints less frequently with rare cases of behavior alteration. Penicillin belongs to the beta-lactam antibiotics and is most commonly used to treat rheumatic fever although it has potential to cause allergic reactions affecting 10% of patients who exhibit IgE-mediated immunological reactions. Here, we present a case of a female diagnosed with PCOS who after treatment with metformin for more than two years, reported with hyperuricemia, migraine, neurological pain, severe joint and knee pains on shoulders and legs, and rheumatic fever. After treatment with benzathine benzyl penicillin for rheumatic fever, the patient also exhibited Type IV delayed hypersensitivity reaction.

Muslim Scholars' Knowledge, Attitudes and Perceived Barriers Towards Polio Immunization in Pakistan.

Pakistan is one of the two countries where polio remains endemic. Among multiple reasons of polio prevalence, false religious beliefs are accounted as major barriers towards polio immunization in Pakistan. Within this context, religious scholars are now engaged in polio immunization campaigns to dismantle the myths and battle the resurgence of polio in Pakistan. The objective of this study was to assess knowledge, attitudes and perceived barriers of Muslim scholars towards polio immunization in Pakistan. A descriptive, cross-sectional survey of Muslim scholars was conducted in Quetta and Peshawar divisions of Pakistan. From October to December 2015, a convenience sample of 770 Muslim scholars was recruited from the local mosques and religious institutions to participate in this study. Knowledge, attitudes, and perceived barriers were assessed by using self-administered, anonymous and pretested questionnaire. Descriptive and regression analyses were used to express the results with p < 0.05 taken as significant. Three hundred and forty-eight (45.2 %) participants exhibited good knowledge about polio with a mean score of 7.16 ± 2.12 (based on 14 questions). Knowledge gaps were identified about the transmission (32.6 %) and consequences of poliovirus (39.9 %). Overall, 527 (68.4 %) participants showed positive attitudes towards polio immunization with a mean attitude score of 27.35 ± 2.68 (based on nine statements). The majority of participants agreed on the need of depoliticizing polio immunization issues (87.1 %), while reservations were noted about their willingness to participate in future polio immunization programs (44.6 %). Security (75.8 %) and vaccine management issues (64 %) were reported by the participants as the major barriers towards polio immunization in Pakistan. The findings showed poor knowledge of Muslim scholars towards polio; however, their attitudes were positive towards polio immunization. More studies are required to assess the knowledge and attitudes of Muslim scholars at the national level to validate the findings of this study.